Our goal is to understand two aspects of gene regulation: 1) the mechanisms that operate to 'open' chromatin and 2) those that dictate how a particular gene within an open multi-gene cluster is chosen for expression. The model evolving from studies of the human beta-globin cluster is that control elements upstream of the genes provide a locus activation function. These upstream elements also increase the expression of the nearest available genes, with availability determined by the promoter. Human diseases with defects in each of these processes are known (eg. beta-thalassemia (Hispanic form) and hereditary persistence of fetal hemoglobin). Knowledge of these topics is part of the background needed for a rational approach to gene therapy. We previously demonstrated that the chicken beta(A)-globin gene and its 3' enhancer contain information sufficient to guarantee copy-number dependent expression in transgenic mice, independent of the site of transgene integration (this property defines a locus control region, LCR). To study the way in which an enhancer/locus control region activates chromatin, we examined transgenic mice carrying various combinations of the chicken beta(A)-globin gene coding region, promoter and 3' enhancer/LCR. The results support a 'mutual interaction' model for the mechanism of chromatin opening by LCRs in which an enhancer/LCR and a promoter must cooperate to generate open chromatin.